++
++
A 39-year-old woman presents with raised rings on her right hand. Not knowing the correct diagnosis, another physician prescribed topical steroids and antifungal medicines with no benefit. The diagnosis of granuloma annulare (GA) was made by the typical clinical appearance, and the patient was offered intralesional steroids. Triamcinolone acetonide was injected as seen in Figure 182-1A. The patient noted improvement over the subsequent weeks, but within a month new lesions began to appear on her other hand (Figure 182-1B). Additional injections were provided and 1 month later the patient had regression of the treated lesions but had new lesions on the right arm (Figure 182-2A). At the next visit, the patient had new lesions on her feet as well (Figure 182-2B). The diagnosis of disseminated GA was made and systemic treatment was started.
++
++
++
GA is a common dermatologic condition that presents as small, light-red, dermal papules coalescing into annular plaques without scale. As in the above vignette, it is often mistaken for nummular eczema or tinea corporis. Distribution, pattern, and lack of scale are important diagnostic clues.
++
GA affects twice as many women as men.1
The four presentations of GA are localized, disseminated/generalized, perforating, and subcutaneous.
Of the four variations, the localized form is seen most often.1
+++
ETIOLOGY AND PATHOPHYSIOLOGY
++
Benign cutaneous, inflammatory disorder of unknown origin.1
Disease may be self-limiting, but may persist for many years.
Reported associations include diabetes mellitus, viral infections (including HIV), Borrelia and streptococcal infections, insect bites, lymphoma, tuberculosis, and trauma.2,3
One proposed mechanism for GA is a delayed-type hypersensitivity reaction as a result of T-helper–type cell (Th)-1 lymphocytic differentiation of macrophages. These macrophages become effector cells that express tumor necrosis factor (TNF)-α and matrix metalloproteinases. The activated macrophages are responsible for dermal collagen matrix degradation.4
An association between high expression of gil-1 oncogene and granulomatous lesions of the skin, including GA, has been established.5
++
The only identifiable risk factor is being a woman. There are several associations, but nothing has been shown to be causative.
++
Annular lesions have raised borders that are skin-colored to erythematous (see Figures 182-1 and 182-2). The rings may become hyperpigmented or violaceous (see Figure 182-2B). There is often a central depression within the ring. These lesions range from 2 mm to 5 cm. Although the classical appearance of GA is annular, the lesions may be arcuate instead of forming a complete ring (Figure 182-3). Most importantly, there should be no scaling as seen in tinea corporis (ringworm).
++
++
Each of the four types of GA has a different distribution. Localized and disseminated GA differ only in that disseminated lesions can spread to the trunk and neck and may be more pronounced in sun-exposed areas.6
++
Localized—This is the most common form of GA, affecting 75% of GA patients.1 It typically presents as solitary lesions on the dorsal surfaces of extremities, especially of hands and feet (Figure 182-4).
Disseminated or generalized—Adults are most affected by this form, which begins in the extremities and can spread to the trunk and neck (Figure 182-5).
Perforating—Children and young adults present with 1 to hundreds of 1- to 4-mm annular papules that may coalesce to form a typical annular plaque. Although this form can appear anywhere on the body, it has an affinity for extremities, especially the hands and fingers.7 The papules may exude a thick and creamy or clear and viscous fluid.
Subcutaneous—These lesions present as rapidly growing, nonpainful, subcutaneous or dermal nodules on the extremities, scalp, and forehead. Subcutaneous GA mainly affects children, with a mean age of 3.9 years (Figure 182-6).6 These lesions are often ill defined and less discrete.
++
++
++
++
Often a diagnosis of GA is made on clinical presentation alone, without the need for biopsy. Subcutaneous GA may be an exception, as the unusual appearance may be mistaken for a rheumatoid nodule. Histologic examination reveals an increase of mucin, which is a hallmark of GA. There is also a dense infiltrate of histiocytes in the mid-dermis and sparse perivascular lymphocytic infiltrate. The histiocytes are either organized as palisading cells lining a collection of mucin or as a diffuse interstitial pattern. There are no signs of epidermal change.3
+++
DIFFERENTIAL DIAGNOSIS
++
Tinea corporis has a raised, scaling border and can present on any body surface. KOH preparation reveals hyphae with multiple branches (see Chapter 144, Tinea Corporis).
Erythema annulare centrifugum has an affinity for thighs and legs. The diameter of these lesions can expand at a rate of 2 to 5 mm/day and may present with a trailing scale inside the advancing border.2 Biopsy is helpful to differentiate this condition from GA, but may be made on clinical findings alone as GA does not have scale (see Chapter 215, Erythema Annulare Centrifugum).
Sarcoidosis—Often presents as red-brown dermal papules without scale on the head and neck. Biopsy will help distinguish sarcoidosis from GA (see Chapter 184, Sarcoidosis).
Nummular eczema presents commonly on extremities, but is almost always associated with scaling plaques and intense itching (see Chapter 154, Nummular Eczema).
Pityriasis rosea often has oval lesions with a trailing collarette of scale. The lesions are minimally raised and have scale that is absent in GA (see Chapter 159, Pityriasis Rosea).
Rheumatoid nodules may mimic appearance of subcutaneous GA. These nodules are often seen over the elbows, fingers, and other joints in a patient with joint pains and other clinical signs of arthritis (see Chapter 99, Rheumatoid Arthritis). Rheumatoid nodules have fibrin deposition on histologic examination, in contrast to mucin in GA.
++
The evidence for various treatments is at best a small series of cases that are not randomized controlled trials. This disease is asymptomatic, and treatments only improve cosmetic appearance. Many patients may want intervention, as diffuse lesions can cause psychological distress. Although GA will eventually resolve, some treatments may cause pigment change or atrophy that might be permanent. Several of the treatments below have shown promise, but these treatments may appear to work when in fact the resolution was natural.
++
In a retrospective study of children with localized GA (mean age: 8.6 years), 39 of 42 presented with complete clearance within 2 years. The average duration was 1 year. Researchers of this study consider most treatments unnecessary because of the self-limiting nature of this variation.7 One treatment option is watchful waiting.8 SORⒷ
Intralesional corticosteroids can be injected into GA lesions with resolution of the area injected (see Figure 182-1). Inject directly into the ring itself with 3 to 5 mg/mL triamcinolone acetonide (Kenalog) using a 27-gauge needle. SORⒸ A large completed ring may take 4 injections to reach 360 degrees of the circle. The major complications include hypopigmentation (see Figure 182-2A) and skin atrophy at the injected sites.
++
Cryotherapy was studied using nitrous oxide for 9 patients and liquid nitrogen for 22 patients. The results showed 80% clearing after a single freeze; however, 4 of 19 patients treated with liquid nitrogen developed atrophic scars when lesions were larger than 4 cm. All patients developed blisters.9 Cryoatrophy may possibly be prevented by avoiding freeze–thaw cycles greater than 10 seconds and not overlapping treatment areas.10 SORⒸ
A 53-year-old Hispanic woman with GA on the dorsal surface of both hands agreed to treatment with cryotherapy on the right hand and intralesional steroids on the left hand (Figure 182-7). Cryotherapy was performed using a 9- to 10-second freeze time and a single freeze. The intralesional injections were performed with a 30-gauge needle and 5 mg/mL triamcinolone (10 mg/mL diluted 1:1 with 1% lidocaine). During the treatment the patient rated the pain from cryotherapy as 9 out of 10 and intralesional steroid 2 out of 10. Figure 182-7 shows the initial lesions and final results after 1 month. The patient was happy with the results of intralesional steroid and disappointed with the results of the cryotherapy. The lesion treated with cryotherapy did not resolve, and spotted areas of hyperpigmentation and hypopigmentation occurred. Upon questioning, the patient states that the lesion treated with cryotherapy was painful for many days, whereas she had no residual pain from the lesion treated with intralesional steroid. The patient then asked for the two remaining lesions on her right hand to be injected with steroid. Although this is a single case example, we could find no published studies of a head-to-head comparison between these commonly used methods for local treatment of GA.
++
+++
GENERALIZED/DISSEMINATED GA
++
++
Recent case reports show that generalized disease responds well to antimalarial treatment. In a retrospective review of patients treated for generalized granuloma annulare, 10 of 18 patients improved after 3 months of treatment with hydroxychloroquine therapy 400 mg daily; by 6 months of therapy most lesions had resolved.11 SORⒸ
Pentoxifylline, a phosphodiesterase inhibitor, has been used to treat generalized GA with good results.12,13 Although the mechanism of action on treatment is unknown, it may be related to the TNF-α inhibition. Treatment with 400 mg three times a day provided impressive improvement in three months.13 SORⒸ
The combination of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg successfully treated 6 patients with granuloma annulare. All patients had complete clearance after 3 to 5 months of treatment.14 SORⒸ
Successful treatment of 6 patients with GA was achieved with 100 mg of dapsone, once a day. Complete clearance in all patients took between 4 weeks and 3 months.15 SORⒸ
UVA1 phototherapy provided good or excellent results in 10 of 20 patients with disseminated GA. In patients with only a satisfactory treatment response, the disease reappeared soon after phototherapy was discontinued.16 SORⒸ
Adalimumab resulted in rapid improvement of granuloma annulare lesions in 7 patients.17 Three patients remained in remission after discontinuing therapy, while 2 patients had recurrence. When the patients with recurrent disease were placed back on adalimumab, their lesions cleared again within 11 weeks. SORⒸ
++
In a study of 4 patients, topical 5% imiquimod cream was effective when used once daily for an average of 2 months. After discontinuing treatment, 3 patients went an average of 12 months without recurrence; the fourth patient had a recurrence 10 days after treatment stopped, but after an additional 6 weeks of applying cream once daily, he was lesion-free for 18 months.18 SORⒸ
Four patients were treated with twice-daily topical application of 0.1% tacrolimus ointment for 6 weeks; all reported improvement after 10 to 21 days. At treatment conclusion, two patients had complete clearance and the other two had marked improvement.19 SORⒸ
Treatment with 0.5 to 1 mg/kg of isotretinoin daily has produced some positive results across multiple small studies; however, because of the potential for adverse effects, this option should be reserved for the most severe, nonresponsive cases in patients who are at low risk for the adverse effects of isotretinoin.20 SORⒸ
Three patients were treated with vitamin E 400 IU daily and zileuton 2400 mg daily. All responded within 3 months with complete clinical clearing.21 SORⒸ
+++
PERFORATING, SUBCUTANEOUS
++
++
In 50% of cases there is spontaneous resolution within 2 years; however, recurrence rate is as high as 40%.22 Patients with skin of color may have postinflammatory hyperpigmentation once the papules and plaques resolve.
++
Follow-up visits should be offered to patients who want active treatment.
++
It is important to reassure patients that this disease is self-limiting. Despite a displeasing appearance, the best treatment may be to let lesions resolve naturally. Numerous individual case studies and treatments have been attempted without consistent success. Treatments may produce side effects that are equally as unwanted, but more permanent, than the GA.
++
++
1. +
Cyr
PR. Diagnosis and management of granuloma annulare.
Am Fam Physician. 2006;74(10):1729–1824.
[PubMed: 17137003]
3. +
Ko
CJ, Glusac
EJ, Shapiro
PE. Noninfectious granulomas. In: Elder
DE, ed. Lever's Histopathology of the Skin, 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:361–364.
4. +
Fayyazi
A, Schweyer
S, Eichmeyer
B,
et al. Expression of IFN-gamma, coexpression of TNF-alpha and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare.
Arch Dermatol Res. 2000;292:384–390.
[PubMed: 10994772]
5. +
Macaron
NC, Cohen
C, Chen
SC, Arbiser
JL. gli-1 Oncogene is highly expressed in granulomatous skin disorders, including sarcoidosis, granuloma annulare, and necrobiosis lipoidica diabeticorum.
Arch Dermatol[Archives of Dermatology Full Text]. 2005;141:259–262.
[PubMed: 15724024]
6. +
Habif
TP. Clinical Dermatology, 4th ed. St Louis, MO: Mosby; 2004.
7. +
Smith
MD, Downie
JB, DiCostanzo
D. Granuloma annulare.
Int J Dermatol. 1997;36:326–333.
[PubMed: 9199977]
8. +
Martinón-Torres
F, Martinón-Sánchez
JM, Martinón-Sánchez
F. Localized granuloma annulare in children: a review of 42 cases.
Eur J Pediatr. 1999;158(10):866.
[PubMed: 10486097]
9. +
Blume-Peytavi
U, Zouboulis
CC, Jacobi
H,
et al. Successful outcome of cryosurgery in patients with granuloma annulare.
Br J Dermatol. 1994;130(4):494–497.
[PubMed: 8186116]
10. +
Lebwohl
MG, Berth-Jones
M, Coulson
I. Treatment of Skin Disease, Comprehensive Therapeutic Strategies, 2nd ed. St. Louis, MO: Mosby; 2006:251.
11. +
Grewal
SK, Rubin
C, Rosenbach
M. Antimalarial therapy for granuloma annulare: results of a retrospective analysis.
J Am Acad Dermatol. 2017:76(4):765–767.
[PubMed: 28325398]
12. +
Lukács
J, Schliemann
S, Elsner
P. Treatment of generalized granuloma annulare—a systematic review.
J Eur Acad Dermatol Venereol. 2015;29(8):1467–1480.
[PubMed: 25651003]
13. +
Nambiar
KG, Jagadeesan
S, Balasubramanian
P, Thomas
J. Successful treatment of generalized granuloma annulare with
pentoxifylline.
Indian Dermatol Online J. 2017;8(3):218–220.
[PubMed: 28584765]
15. +
Czarnecki
DB, Gin
D. The response of generalized granuloma annulare to
Dapsone.
Acta Derm Venereol (Stockh). 1986;66:82–84.
16. +
Schnopp
C, Tzaneva
S, Mempel
M,
et al. UVA1 phototherapy for disseminated granuloma annulare.
Photodermatol Photoimmunol Photomed. 2005;21(2):68–71.
[PubMed: 15752123]
17. +
Min
MS, Lebwohl
M. Treatment of recalcitrant granuloma annulare (GA) with
adalimumab: a single-center, observational study.
J Am Acad Dermatol. 2016;74(1):127.
[PubMed: 26552891]
18. +
Badavanis
G, Monastirli
A, Pasmatzi
E, Tsambaos
D. Successful treatment of granuloma annulare with
imiquimod cream 5%: a report of four cases.
Acta Derm Venereol. 2005;85(6):547–548.
[PubMed: 16396814]
19. +
Jain
S, Stephens
CJM. Successful treatment of disseminated granuloma annulare with topical
tacrolimus.
Br J Dermatol. 2004;150:1042–1043.
[PubMed: 15149532]
21. +
Smith
KJ, Norwood
C, Skelton
H. Treatment of disseminated granuloma annulare with a 5-lipoxygenase inhibitor and vitamin E.
Br J Dermatol. 2002;146(4):667–670.
[PubMed: 11966702]
22. +
Reisenauer
A, White
KP, Korcheva
V, White
CR. Non-infectious granulomas. In: Bolognia
JL, Jorizzo
JL, Schaffer
JV, eds. Dermatology, 2nd ed. Philadelphia, PA: Elsevier; 2012.